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Adipose-tissue Tregs: important players in immunological control of metabolism

Award Number: R01DK092541
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2011
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Adipose-tissue Tregs: important players in immunological control of metabolism - Foxp3+CD4+ regulatory T cells (Tregs) control most types of immune responses. Recently, distinct compartments of tissue-localized Tregs that help maintain local homeostasis were also discovered. These so- called “tissue-Tregs” have transcriptomes, TCR repertoires and growth/survival factor dependencies that differ from those of lymphoid-organ Tregs and of Tregs in other tissues. Tissue-Tregs regulate non-immunological processes such as metabolism and regeneration via influences on innate and adaptive immunocytes as well as on local stromal and parenchymal cells. A paradigmatic tissue-Treg compartment, first reported by the PI's lab in 2009, is that found in visceral adipose tissue (VAT), especially the epidydimal VAT (eVAT) depot of lean mice. eVAT Tregs, which depend on the supreme regulator of adipogenesis, PPARγ, for effective accrual and function, help assure local and systemic metabolism, notably insulin sensitivity. This important function is known to reflect direct eVAT-Treg influences on local immunocytes and on eVAT-resident, immunocyte-promoting mesenchymal stromal cells (VmSCs). The focus of this proposed project is on a newly discovered function of eVAT Tregs. Our preliminary data, primarily derived from transcriptomic analyses and in vitro adipogenesis assays, indicate that they control the differentiation of stroma-resident adipocyte precursor cells into mature adipocytes (and potentially adipocyte turnover and fibrosis). Moreover, these data point to Oncostatin M (OSM) as a potential mediator of these influences. THE MAJOR GOAL OF THIS PROPOSED PROJECT IS TO ELUCIDATE THE AVENUES OF COMMUNICATION BETWEEN eVAT Tregs AND ADIPOCYTE PRECURSORS. We propose: (1) To determine the extent to which OSM production by eVAT-Tregs is responsible for their constraint of stroma- resident adipocyte precursors. This Aim addresses the need to validate our transcriptomic and in vitro adipogenesis data with in vivo examinations. (2) To evaluate the effects of aging on eVAT-Treg control of local inflammation and adipogenesis. Discrepancies in the literature imply that the impact of eVAT Tregs may be very different in aging vs old mice. We propose to evaluate this notion in a head-to-head comparison of mice specifically lacking eVAT-Tregs or not. (3) To determine whether and how eVAT-Treg control of adipocyte differentiation shows sexual dimorphism. Male and female rodents and humans differ in the deposition and function of their adipose tissue. A recent report (on which the PI's lab collaborated) highlights a male:female dichotomy in IL-33-producing, immunocyte- promoting VmSCs, leading to a dimorphism in gonadal VAT accrual. Our preliminary data uncovered a difference in adipocyte dynamics as well, which is the focus of this Aim. Upon successful completion of this proposed project, we should know in what contexts eVAT-Tregs regulate adipocyte dynamics and how they do so. This represents a novel function of eVAT Tregs, one that fits within the emerging theme of tissue-Treg control of stem/progenitor cell activities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $423,750 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	5/4/2026	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2025 ( Subtotal = $423,750 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	7/10/2025	NON-COMPETING CONTINUATION	$423,750
2025	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $423,750

Issue Date FY: 2024 ( Subtotal = $406,800 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	5/7/2024	NON-COMPETING CONTINUATION	$406,800
														Subtotal = $406,800

Issue Date FY: 2023 ( Subtotal = $423,750 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	5/19/2023	COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/22/2022	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/27/2021	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	4/23/2020	NON-COMPETING CONTINUATION	$423,750
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	2/20/2020	COMPETING CONTINUATION	$158,158
2020	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/20/2020	NON-COMPETING CONTINUATION	-$158,158
														Subtotal = $423,750

Issue Date FY: 2019 ( Subtotal = $423,750 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/18/2019	COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2018 ( Subtotal = $381,375 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/13/2018	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2017 ( Subtotal = $381,375 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/21/2017	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2016 ( Subtotal = $381,375 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/12/2016	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2015 ( Subtotal = $381,375 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/31/2015	COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2014 ( Subtotal = $375,443 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/20/2014	NON-COMPETING CONTINUATION	$375,443
														Subtotal = $375,443

Issue Date FY: 2013 ( Subtotal = $362,214 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/11/2013	NON-COMPETING CONTINUATION	$362,214
														Subtotal = $362,214

Issue Date FY: 2012 ( Subtotal = $374,335 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/1/2012	NON-COMPETING CONTINUATION	$374,335
														Subtotal = $374,335

Issue Date FY: 2011 ( Subtotal = $423,750 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/11/2011	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $6,434,292

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Adipose-tissue Tregs: important players in immunological control of metabolism

Award Number: R01DK092541

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/12/2011

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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